Diamine alkylene diacetic or triacetic acid derivatives, preparation method, use in cosmetic and pharmaceutical compositions and compositions containing them

ABSTRACT

Novel alkylenediaminediacetic acid or alkylenediaminetriacetic derivatives of formula (I):                    
     or an organic or inorganic salt thereof, their process of preparation, and their use in cosmetic and pharmaceutical compositions, such as for protecting the body against oxidative stress are discussed.

This is a continuation of application Ser. No. 09/297,748, filed Jul.14, 1999, now U.S. Pat. No. 6,218,432 B1, which was the National StageApplication of International Application No. PCT/FR98/01877, filed Sep.1, 1998, each of which are incorporated herein by reference.

The subject-matter of the present invention is novel compounds of thetype of esters derived from alkylenediaminediacetic acid oralkylenediaminetriacetic acid and in particular their use in cosmeticand pharmaceutical compositions, in particular for protecting the bodyagainst oxidative stress.

Oxidative stress characterizes a certain number of physiological andphysiopathological situations during which there exists an imbalance inthe antioxidant/prooxidant balance. This imbalance is reflectedessentially by uncontrolled oxidative processes within living tissueswhich involve oxygen-comprising free radicals and which lead to theformation of oxidative damage in biological molecules andmacromolecules.

A certain number of physiopathological situations induce, promote,accompany and/or are the direct consequence of oxidative stress. Theyare in particular inflammation, ageing, neurodegenerative diseases,exposure to UV radiation and to ionizing radiation, carcinogenesis, orthe toxicity and/or mode of action of certain medicaments.

It is known that, during oxidative stress, iron is released from itsnormal storage sites, such as ferritin, and then becomes available toparticipate in certain reactions, in particular in Fenton andHaber-Weiss reactions, thus making possible the formation of hydroxylradicals, the latter being known to be responsible for much oxidativedamage.

Compounds, in particular synthetic compounds, which make it possible toprotect the body against oxidative stress have been sought for a longtime.

These compounds can be grouped into the following main classes:

antilipoperoxidizing agents, such as vitamin E, trolox orbutylhydroxytoluene,

biological reducing agents, such as reduced glutathione and itsderivatives or vitamin C and its derivatives,

singlet oxygen deactivators (quenchers), such as β-carotene,

systems capable of decomposing hydrogen peroxide and in particularenzymes, such as catalase or peroxidases, in the presence of theirco-substrates,

systems for protecting against the superoxide anion, such as superoxidedismutase (SOD) or SOD-like materials, such as the Mn-desferal complexor copper diisopropyl salicylate,

systems capable of decomposing organic hydroperoxides, such asglutathione peroxidase or selenium-based model systems,

iron-chelating agents, such as desferal or certain hydroxypyridinones.

However, none of the known iron-chelating agents proved to be reallysatisfactory for the purpose of protecting the body with regard tohydroxyl radicals. Most of these protective compounds are toxic becauseof interference with the normal metabolism of iron, which limits theiruse.

Patent Application WO-94/11338 discloses novel iron-chelating agentswhich are effective against oxidative stress. These compounds, which arecapable of forming complexes with iron, have low stability constants,which consequently decreases the toxicity risks associated with theiruse.

The action of these compounds is based on a novel concept, that ofiron-chelating agents which can be activated in a situation of oxidativestress.

The advantage of these compounds is in particular that of limiting thepotential side effects. This is because, in a normal situation, thesecompounds have an affinity for iron which is sufficiently weak not todisplace iron from transport proteins, such as transferrin, unlikecertain other powerful chelating agents, such as desferal or HBED, whichhave high stability constants (greater than 10³⁰). In a situation ofoxidative stress, these compounds are specifically oxidized by H₂O₂ tospecies having a strong affinity for iron which prevent itsparticipation in the formation of HO^(•), resulting in the term “ofactivation in a situation of oxidative stress”.

A number of in vitro experiments have confirmed the advantage of thesecompounds as protective agents with regard to the induction of oxidativedamage catalysed by iron in the various classes of biological molecules.

However, the protective effect of these compounds of the prior art oncultured cells remains relatively modest because their bioavailabilityremains low, even when the compounds are provided in the form of alkylesters.

The aim of the present invention is to solve this problem by providingnovel compounds which are effective against oxidative stress and whichconfer very effective protection against the toxicity of H₂O₂ oncultured cells.

The subject-matter of the invention is therefore a compound of formula(I):

in which:

R₁, R₂ and R₃ are, independently of one another, chosen from H, OH or alinear or branched C₁-C₈ alkoxy radical

R₄ and R₅ are, independently of one another, chosen from H or a linearor branched C₁-C₄ alkyl radical; it being possible for R₄ and R₅, takentogether, to form a 5- or 6-membered ring

X₁ and X₂ are, independently of one another, chosen from:

a —(CO)NR₆R₇ group in which R₆ and R₇ are, independently of one another,chosen from H or a linear or branched C₁-C₄ alkyl radical; it beingpossible for R₆ and R₇, taken together, to form a 5- or 6-membered ring,or

an —O(CO)R₈ group in which R₈ is chosen from H or a linear or branchedC₁-C₈ alkyl radical

Z is chosen from a group of formula A or a group of formula B

in which:

R′₁, R′₂ and R′₃ are, independently of one another, chosen from H, OH ora linear or branched C₁-C₈ alkoxy radical

X′ is either a —(CO)NR′₄R′₅ group in which R′₄ and R′₅ are,independently of one another, chosen from H or a linear or branchedC₁-C₄ alkyl radical; it being possible for R′₄ and R′₅, taken together,to form a 5-or 6-membered ring; or an —O(CO)R′₆ group in which R′₆ ischosen from H or a linear or branched C₁-C₈ alkyl radical and itsorganic or inorganic salts.

Another subject-matter of the invention is a process for the preparationof the above compounds in which a salt, for example a sodium salt or ahydrochloride, of an N,N′-dibenzylalkylenediamine-N,N′-diacetic acidderivative or N-benzylalkylenediamine-N,N′,N′-triacetic acid derivativeis reacted with 2 to 4 equivalents of a substituted halomethylderivative.

Another subject-matter of the invention is a cosmetic or pharmaceuticalcomposition comprising, in a cosmetically or pharmaceutically acceptablevehicle, at least one compound of above formula (I).

Another subject-matter of the invention is the use of the compounds offormula (I) as antioxidizing agent.

Another subject-matter of the invention is the use of the compounds offormula (I) in a cosmetic composition for treating oxidative stressand/or for treating the effects of exposure to the sun and/or forpreventing ageing, in particular of the skin or hair.

Another subject-matter of the invention is the use of the compounds offormula (I) for the preparation of a pharmaceutical composition intendedto treat oxidative stress, in particular related to certain pathologicalconditions, and/or intended to treat pathological situations, such ascancers, inflammatory conditions, reinfusion ischaemia, iron overloadsor degenerative diseases of the nervous system, and/or intended to treatthe effects of exposure to ionizing or solar radiation, and/or intendedto treat the effects of the use of certain medicaments which generatefree radicals, and/or intended to prevent ageing, in particular of theskin or hair.

It has therefore been found that the compounds of the invention exert aprotective effect at low concentrations, of the order of a fewmicromoles per liter, whereas the compounds of the closest prior art,such as WO 94/11338, only exert an effect at much higher concentrations,of the order of a millimole per liter.

The compounds according to the invention are therefore much moreeffective than those of the prior art with respect to the protection ofcultured cells against the toxicity of H₂O₂.

The compounds according to the invention are therefore esters ofN,N′-dibenzylalkylenediamine-N,N′-diacetic acid derivatives orN-benzylalkylenediamine-N,N′,N′-triacetic acid derivatives.

They correspond to the above general formula (I).

The alkoxy radicals are preferably chosen, independently of one another,from methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy,sec-butyloxy or tert-butyloxy radicals.

The alkyl radicals are preferably chosen, independently of one another,from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ortert-butyl radicals. When they form a ring, the said ring is preferablya cyclohexyl.

The compounds according to the invention can also be provided in theform of inorganic or organic acid salts.

Mention may be made, among inorganic salts, of sulphates,hydrochlorides, nitrates, phosphates or bromates.

Mention may be made, among organic salts, of fumarates, mesylates ortosylates.

Mention may in particular be made, among the preferred compoundsaccording to the invention, of:

bis(acetoxymethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]ethylenediamine-N,N′-diacetate,

bis(pivaloyloxymethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]ethylenediamine-N,N′-diacetate, and

bis(N,N-diethylaminocarbonylmethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]ethylenediamine-N,N′-diacetate, andtheir salts, in particular their hydrochlorides.

The compounds according to the invention can be prepared by a personskilled in the art on the basis of his overall knowledge according toconventional synthetic methods.

This preparative process can consist in particular in reacting a salt,for example a sodium salt or a hydrochloride, of anN,N′-dibenzylalkylenediamine-N,N′-diacetic acid derivative orN-benzylalkylenediamine-N,N′,N′-triacetic acid derivative with 2 to 4equivalents of a substituted halomethyl derivative.

Mention may be made, among substituted halomethyl derivatives, by way ofexample, of bromomethyl acetate or chloromethyl pivalate.

The reaction can take place in DMF at a temperature of 35-60° C.,preferably 40-50° C., for 20-30 hours, preferably 22-26 hours.

The product obtained can subsequently be purified, for example bychromatography on a silica column.

The compounds according to the invention can be used as activesubstances for protecting from the harmful effects of free radicals,that is to say against oxidative stress, and in particular for treatingpathological situations in human or veterinary medicine, such ascancers, inflammatory conditions, reinfusion ischaemia, iron overloadsor degenerative diseases of the nervous system, or for treating theeffects of exposure to ionizing or solar radiation, or for treating theeffects of the use of certain medicaments known to generate freeradicals, in particular anticancers, such as adriamycin.

These compounds can also be used in non-pathological situations, such asexposure to the sun or ageing, in order in particular to protect theskin or hair.

The compositions, in particular cosmetic or pharmaceutical compositions,comprising one or more compounds according to the invention can beprovided in various conventional forms, such as in the form of a salve,cream, ointment, gel, spray, lotion, emulsion or vesicular dispersion.

The compound of formula (I) can be present in an amount of 0.001 to 10%by weight with respect to the total weight of the composition,preferably in a proportion of 0.01 to 8% by weight, preferably of 0.1 to5% by weight.

When the composition is a pharmaceutical composition, it can beadministered in any conventional administration form, such as orally,topically or parenterally, the pharmaceutically acceptable vehicledepending on the administration form chosen.

The pharmaceutical dosage form and the amount of compound present in thecomposition can be easily determined by a person skilled in the art onthe basis of his overall knowledge.

In the compositions according to the invention, the compound of formula(I) can be used in combination with at least one other active substance,in particular a substance for combating free radicals.

These substances can be chosen from:

antilipoperoxidizing agents, such as vitamin E, trolox orbutylhydroxytoluene,

biological reducing agents, such as reduced glutathione and itsderivatives or vitamin C and its derivatives,

singlet oxygen deactivators (quenchers), such as β-carotene,

systems capable of decomposing hydrogen peroxide and in particularenzymes, such as catalase or peroxidases, in the presence of theirco-substrates,

systems for protecting against the superoxide anion, such as superoxidedismutase (SOD) or SOD-like materials, such as the Mn-desferal complexor copper diisopropyl salicylate,

systems capable of decomposing organic hydroperoxides, such asglutathione peroxidase or selenium-based model systems,

iron-chelating agents, such as desferal or certain hydroxypyridinones.

The compound according to the invention can also be used in combinationwith anti-inflammatories, UV screening agents and/or penetrationpromoters.

The compound of the formula (I) and the active substance can be combinedwithin the same composition or be applied separately.

The examples below are given for the purpose of illustrating thepreparation of some compounds of formula (I) and some of their uses inthe pharmaceutical and cosmetic fields.

SYNTHETIC EXAMPLE 1

bis(acetoxymethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]-ethylenediamine-N,N′-diacetate offormula:

2 g (3.3 mmol) of N,N′-bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N′-diacetic acid dihydrochloride are dissolved in 20ml of water by addition of sodium hydroxide solution. The pH is broughtto 8 by addition of concentrated hydrochloric acid. The solution isevaporated to dryness and then the residue is taken up in 30 ml ofdimethylformamide.

1.3 g of bromomethyl acetate (BrCH₂OCOCH₃; 8.5 mmol) are added and themedium is stirred at 45° C. for 24 h. The mixture is then evaporated todryness, the residue is then taken up in dichloromethane and thesolution is washed with water, dried over sodium sulphate, filtered andevaporated to dryness.

The residue is purified by chromatography on a silica column (ethylacetate/heptane 3:1 eluent).

An oil is obtained, which oil is purified by crystallization from adichloromethane/pentane mixture.

After filtration and drying, 650 mg of a white solid are obtained(yield: 30%).

NMR spectrum: ¹H and ¹³C (400 MHz) in CDCl₃: conforms to the expectedstructure

Elemental analysis C H N O % calculated 56.46 6.52 4.12 32.91 % found56.24 6.51 4.18 32.66

SYNTHETIC EXAMPLE 2

bis(pivaloyloxymethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]ethylenediamine-N,N′-diacetate offormula:

2 g (3.3 mmol) ofN,N′-bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N′-diacetic aciddihydrochloride are dissolved in 20 ml of water by addition of sodiumhydroxide solution. The pH is brought to 8 by addition of concentratedhydrochloric acid. The solution is evaporated to dryness and then theresidue is taken up in 30 ml of dimethylformamide.

1.5 g of chloromethyl pivalate (ClCH₂OCOtBu; 10 mmol) are added and themedium is stirred at 45° C. for 24 h. The mixture is then evaporated todryness, the residue is then taken up in dichloromethane and thesolution is washed with water, dried over sodium sulphate, filtered andevaporated to dryness. The residue is purified by chromatography on asilica column (dichloromethane/methanol 99:1 eluent).

500 mg of a colourless oil are obtained (yield: 20%).

NMR spectrum: ¹H (400 MHz) in CDCl₃: conforms to the expected structure

SYNTHETIC EXAMPLE 3

bis(N,N-diethylaminocarbonylmethyl)[N,N′-bis(3,4,5-trimethoxybenzyl)]ethylenediamine-N,N′-diacetatedihydrochloride of formula:

2 g (3.3 mmol) ofN,N′-bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N′-diacetic aciddihydrochloride are dissolved in 20 ml of water by addition of sodiumhydroxide solution. The pH is brought to 8 by addition of concentratedhydrochloric acid. The solution is evaporated to dryness and then theresidue is taken up in 30 ml of dimethylformamide.

1.0 g of 2-chloro-N,N-diethylacetamide (ClCH₂CONEt₂; 6.6 mmol) and 0.1 gof methyl iodide are added and then the medium is stirred at 45° C. for24 h. The mixture is then evaporated to dryness, the residue is thentaken up in dichloromethane and the solution is washed with water, driedover sodium sulphate, filtered and evaporated to dryness. The residue ispurified by chromatography on a silica column (ethyl acetate eluent).

The oil obtained is taken up in ethanol. A white precipitate appears onaddition of concentrated hydrochloric acid. This precipitate is filteredoff, washed with ether and dried under vacuum.

650 mg of a white solid are obtained (yield: 25%)

NMR spectrum: ¹H (400 MHz) in CDCl₃: conforms to the expected structure

EXAMPLE 4

Demonstration of the Activity of the Compounds

The activity of the compounds was evaluated by their ability to protectV79 cells against the toxicity of H₂O₂, a technique conventionally usedto evaluate the effectiveness of antioxidants or iron-chelating agents.

The activity of the compound of Example 1 was compared with that of twocompounds of the prior art disclosed in W094/11338:

Comparative 1: the dihydrochloride ofN,N′-bis(3,4,5-trimethoxybenzyl)ethylenediamine-N,N′-diacetic acid offormula:

Comparative 2: its methyl ester of formula

a) Experimental Protocol

V79 cells were subcultured in DMEM (Dulbecco Modified Essential Medium)medium supplemented with 10% of foetal calf serum, streptomycin,penicillin and glutamine at 37° C. under an atmosphere of 95% air+5%CO₂.

The cells were subsequently seeded at a density of 5×10³/ml in 96-wellplates.

After 24 hours, the cells were rinsed and then incubated with the testcompounds at different concentrations.

After a contact time of 1 hour, 30 μM of H₂O₂ were added and incubatedat 37° C. for a further one hour.

The cells were subsequently rinsed and then again brought into contactwith the supplemented medium described above.

After 72 hours, the number of cells was evaluated in each well by usingthe neutral red technique.

The protective effect is assessed by the IC₅₀, which measures theconcentration which induces 50% protection against cytotoxicity incomparison with the wells treated only with H₂O₂.

b) Results

The following results were obtained:

Result (concentration inducing 50% Compound protection) Compound ofExample 1 10 μM Comparative 1 25% protection only at 10 mM Comparative 2greater than 1 mM (compound insoluble beyond this point)

It is therefore found that the compound according to the inventionexerts a much more pronounced protective effect than those of the twocompounds of the prior art.

EXAMPLE 5

A cosmetic composition which is provided in the form of an emulsion isprepared by using the constituents below (% by weight):

Compound of Example 1 0.1% Oxyethylenated PEG 50   3% Mono/diglycerylstearate   3% Liquid petrolatum  24% Cetyl alcohol   5% Water q.s. for100%

EXAMPLE 6

A cosmetic composition which is provided in the form of an emulsion isprepared by using the constituents below (% by weight):

Compound of Example 1 0.1% Octyl palmitate  10% Glyceryl isostearate  4% Liquid petrolatum  24% Vitamin E   1% Glycerol   3% Water q.s. for100%

The following cosmetic composition is prepared by using the constituentsbelow (% by weight):

Compound of Example 2 0.05%  Jojoba oil  13% Potassium sorbate 0.3%Cyclopentadimethylsiloxane  10% Stearyl alcohol   1% Stearic acid   4%Polyethylene glycol stearate   3% Vitamin E   1% Glycerol   3%Preservatives q.s. Water q.s. for 100%

EXAMPLE 8

A pharmaceutical composition in the form of a drinkable suspension isprepared comprising the following constituents:

Compound of Example 1 0.10 g 90% Ethanol 1.00 g 70% Sorbitol 0.50 gSodium saccharinate 0.01 g Methyl p-hydroxybenzoate 0.04 g Flavouringq.s. Water q.s. for 5 ml

EXAMPLE 9

A pharmaceutical composition in the form of a tablet is preparedcomprising the following constituents:

Compound of Example 1 0.10 g Starch 0.12 g Dicalcium phosphate 0.20 gLactose 0.06 g Magnesium stearate 0.02 g

What is claimed is:
 1. A process for the preparation of a compound offormula (I) or an organic or inorganic salt thereof, comprising reactinga salt of an N,N′-dibenzylalkylenediamine-N,N′-diacetic acid compound oran N-benzylalkylenediamine-N,N′,N′-triacetic acid compound with 2 to 4equivalents of a substituted halomethyl compound, wherein said compoundof formula (I) is chosen from:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals, it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring; X₁ and X₂ are, independently of oneanother, chosen from —(CO)NR₆R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 2. A process according toclaim 1, wherein said salt of anN,N′-dibenzylalkylenediamine-N,N′-diacetic acid compound or anN-benzylalkylenediamine-N,N′,N′-triacetic acid compound is chosen fromsodium salts and hydrochloride salts.
 3. A process according to claim 1,wherein said substituted halomethyl compound is chosen from bromomethylacetate and chloromethyl pivalate.
 4. A process according to claim 1,wherein said reaction is carried out in dimethylformamide at atemperature ranging from 35 to 60° C.
 5. A process according to claim 1,wherein the alkoxy radicals are, independently of one another, chosenfrom methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy,sec-butyloxy and tert-butyloxy radicals and wherein the alkyl radicalsare, independently of one another, chosen from methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl and tert-butyl radicals.
 6. A processaccording to claim 1, wherein said inorganic or organic salt is chosenfrom sulphates, hydrochlorides, nitrates, phosphates, bromates,fumarates, mesylates and tosylates.
 7. A method of preventing theeffects of aging that are associated with the generation of freeradicals comprising applying to the body a cosmetic composition, whereinsaid cosmetic composition comprises at least one ingredient chosen fromcompounds of formula (I) and organic and inorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring: X₁ and X₂ are, independently of oneanother, chosen from

—(CO)NR₆R₇ groups in which R₆ and R₇ are, independently of one another,chosen from H and linear and branched C₁-C₄ alkyl radicals; it beingpossible for R₆ and R₇, taken together, to form a 5- or a 6-memberedring, and —O(CO)R₈ groups in which R₈ is chosen from H and linear andbranched C₁-C₈ alkyl rdicals; Z is chosen from compounds of formula (II)and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 8. A method of claim 7,comprising applying said cosmetic composition to the skin or hair.
 9. Amethod of claim 8, wherein said skin or hair are human skin or hair. 10.A cosmetic or pharmaceutical composition for preventing the effects ofaging that are associated with the generation of free radicals, whereinsaid composition comprises at least one ingredient chosen from compoundsof formula (I) and organic and inorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring; X₁ and X₂ are, independently of oneanother, chosen from —C(CO)NR₆R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formul (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals, wherein said at least oneingredient is present in an amount effective for preventing the effectsof aging that are associated with the generation of free radicals.
 11. Amethod of treating a pathological condition of oxidative stress thatgenerates free radicals, comprising administering to a subject in needthereof a pharmaceutical composition, wherein said pharmaceuticalcomposition comprises at least one ingredient chosen from compounds offormula (I) and organic and inorganic salts thereof: wherein:

R₁, R₂ and R₃ are, independently of one another, chosen form H, OH andlinear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are, independentlyof one another, chosen from H and linear and branched C₁-C₄ alkylradicals; it being possible for R₄ and R₅, taken together, to form a 5-or a 6-membered ring; X₁ and X₂ are, independently of one another,chosen from —(CO)NR₆R₇ groups in which R₆ and R₇ are, independently ofone another, chosen from H and linear and branched C₁-C₄ alkyl radicals;it being possible for R₆ and R₇, taken together, to form a 5- or a6-membered ring, and —O(CO)R₈ groups in which R₈ is chosen from H andlinear and branched C₁-C₈ alkyl radicals; Z is chosen from compounds offormula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 12. A method of treating apathological situation associated with generation of free radicals,comprising administering to a subject in need thereof a pharmaceuticalcomposition, wherein said pharmaceutical composition comprises at leastone ingredient chosen from compounds of formula (I) and organic andinorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring; X₁ and X₂ are, independently of oneanother, chosen from —(CO)NR₆R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 13. The method of claim 12,wherein said pathological situation is chosen from cancers, inflammatoryconditions, reinfusion ischaemias, iron overloads, and degenerativediseases of the nervous system.
 14. A method of treating an effect ofmedicaments which generate free radicals, comprising administering to asubject in need thereof a pharmaceutical composition, wherein saidpharmaceutical composition comprises at least one ingredient chosen fromcompounds of formula (I) and organic and inorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring; X₁ and X₂ are, independently of oneanother, chosen from —(CO)NR₆R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 15. A method of preventing theeffects of aging associated with the generation of free radicals,comprising administering to a subject in need thereof a pharmaceuticalcomposition, wherein said pharmaceutical composition comprises at leastone ingredient chosen from compounds of formula (I) and organic andinorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6-membered ring; X₁ and X₂ are, independently of oneanother, chosen from —(CO)NR₆ R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a 6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.
 16. A method of claim 15,wherein said preventing the effects of aging associated with thegeneration of free radicals occurs in the skin or hair.
 17. Apharmaceutical composition for treating a pathological situationassociated with the generation of free radicals, wherein saidpharmaceutical composition comprises at least one ingredient chosen fromcompounds of formula (I) and organic and inorganic salts thereof:

wherein: R₁, R₂ and R₃ are, independently of one another, chosen from H,OH and linear and branched C₁-C₈ alkoxy radicals; R₄ and R₅ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₄ and R₅, taken together,to form a 5- or a 6 -membered ring; X₁ and X₂ are, independently of oneanother, chosen from —(CO)NR₆R₇ groups in which R₆ and R₇ are,independently of one another, chosen from H and linear and branchedC₁-C₄ alkyl radicals; it being possible for R₆ and R₇, taken together,to form a 5- or a 6-membered ring, and —O(CO)R₈ groups in which R₈ ischosen from H and linear and branched C₁-C₈ alkyl radicals; Z is chosenfrom compounds of formula (II) and formula (III)

in which: R′₁, R′₂ and R′₃ are, independently of one another, chosenfrom H, OH, and linear and branched C₁-C₈ alkoxy radicals; X′ is chosenfrom —(CO)NR′₄R′₅ groups in which R′₄ and R′₅ are, independently of oneanother, chosen from H and linear and branched C₁-C₄ alkyl radicals; itbeing possible for R′₄ and R′₅, taken together, to form a 5- or a6-membered ring, and —O(CO)R′₆ groups in which R′₆ is chosen from H andlinear and branched C₁-C₈ alkyl radicals.